Animal testing

Enos the space chimp before insertion into the Mercury-Atlas 5 capsule in 1961. Non-human primates make up 0.3 percent of research animals, with about 60,000 used each year in the U.S. and 10,000 in the European Union.

Animal testing or animal research refers to the use of non-human animals in experiments. It is estimated that 50 to 100 million vertebrate animals worldwide — from zebrafish to non-human primates — are used annually and killed during or after the experiments. Although much larger numbers of invertebrates are used and the use of flies and worms as model organisms is very important, experiments on invertebrates are largely unregulated and not included in statistics. Sources of laboratory animals vary between countries and species; while most animals are purpose-bred, others may be caught in the wild or supplied by dealers who obtain them from auctions and pounds.

The research is conducted inside universities, medical schools, pharmaceutical companies, farms, defense establishments, and commercial facilities that provide animal-testing services to industry. It includes pure research such as genetics, developmental biology, behavioural studies, as well as applied research such as biomedical research, xenotransplantation, drug testing and toxicology tests, including cosmetics testing. Animals are also used for education, breeding, and defense research.

The topic is highly controversial. Supporters of the practice, such as the British Royal Society, argue that virtually every medical achievement in the 20th century relied on the use of animals in some way, with the Institute for Laboratory Animal Research of the U.S. National Academy of Sciences arguing that even sophisticated computers are unable to model interactions between molecules, cells, tissues, organs, organisms, and the environment, making animal research necessary in some areas. Opponents, such as the British Union for the Abolition of Vivisection, question the necessity of it, arguing further that it is cruel, poor scientific practice, never reliably predictive of human metabolic and physiological specificities, poorly regulated, that the costs outweigh the alleged benefits, or that animals have an intrinsic right not to be used for experimentation.

Definitions

The terms animal testing, animal experimentation, animal research, in vivo testing, and vivisection have similar denotations but different connotations. Literally, "vivisection" means the "cutting up" of a living animal, and historically referred only to experiments that involved the dissection of live animals. The term is now used to refer to any experiment using living animals; for example, the Encyclopaedia Britannica defines "vivisection" as: "Operation on a living animal for experimental rather than healing purposes; more broadly, all experimentation on live animals." For others, the word has a pejorative connotation, implying torture and suffering. The word "vivisection" is preferred by those opposed to this research, whereas scientists typically use the term "animal experimentation."

History

Main article: History of animal testing

One of Pavlov’s dogs with a saliva-catch container and tube surgically implanted in his muzzle. Pavlov Museum, 2005

An Experiment on a Bird in an Air Pump, from 1768, by Joseph Wright.

Claude Bernard, regarded as the "prince of vivisectors" and one of the greatest men of science, argued that experiments on animals are "entirely conclusive for the toxicology and hygiene of man," thereby establishing the paradigm still followed by the scientific community today.

The earliest references to animal testing are found in the writings of the Greeks in the second and fourth centuries BCE. Aristotle (Αριστοτέλης) (384-322 BCE) and Erasistratus (304-258 BCE) were among the first to perform experiments on living animals. Galen, a physician in second-century Rome, dissected pigs and goats, and is known as the "father of vivisection."

In the 1880s, Louis Pasteur convincingly demonstrated the germ theory of medicine by giving anthrax to sheep. In the 1890s, Ivan Pavlov famously used dogs to describe classical conditioning. Insulin was first isolated from dogs in 1922, and revolutionized the treatment of diabetes. On November 3, 1957, a Russian dog, Laika, became the first of many animals to orbit the earth. In the 1970s, a treatment of leprosy was developed in armadillos, then in humans. In 1996, Dolly the sheep was born, the first mammal to be cloned from an adult cell.

Riots between pro- and anti- animal testing factions broke out in the early 1900s over this memorial for a vivisected dog.

As the use of animals increased, so did criticism and controversy. In 1655, physiologist Edmund O'Meara is recorded as saying that "the miserable torture of vivisection places the body in an unnatural state." O'Meara and others argued that animal physiology could be affected by the pain and suffering of vivisection, rendering the results unreliable. There were also objections on an ethical basis, contending that the benefit to humans did not justify the harm to animals. Early objections to animal testing also came from another angle — many people believed that animals are inferior to humans and thus so different that any results obtained from animals would be inapplicable to humans.

On the other side of the debate, those in favor of animal testing held that experiments on living animals were necessary to advance medical and biological knowledge. Claude Bernard, known as the "prince of vivisectors" and the father of physiology — whose wife, Marie Françoise Martin, founded the first anti-vivisection society in France in 1883 — famously wrote in 1865 that "the science of life is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen". Arguing that "experiments on animals ... are entirely conclusive for the toxicology and hygiene of man ... for as I have shown, the effects of these substances are the same on man as on animals, save for differences in degree," Bernard established the paradigm of animal experimentation in scientific method that is largely followed by the scientific community today.

In 1822, the first animal protection law was enacted in the British parliament, followed by the Cruelty to Animals Act (1876), the first law specifically aimed at regulating animal testing. The legislation was promoted by Charles Darwin, who wrote to Ray Lankester in March 1871: "You ask about my opinion on vivisection. I quite agree that it is justifiable for real investigations on physiology; but not for mere damnable and detestable curiosity. It is a subject which makes me sick with horror, so I will not say another word about it, else I shall not sleep to-night."

The growing division between the pro- and anti- animal testing factions first came to dramatic public attention during the Brown Dog riots that raged in the early 1900s in the streets of London, when hundreds of medical students clashed with anti-vivisectionists and police over a memorial to a vivisected dog.

Care and use of animals

See also: Animal testing regulations, Institutional Animal Care and Use Committee, and Animals (Scientific Procedures) Act 1986

Regulations

The regulations that apply to animals in laboratories vary across species. In the U.S., under the provisions of the Animal Welfare Act and the National Institutes of Health's (NIH) Guide for the Care and Use of Laboratory Animals (the Guide), any procedure can be performed on an animal if it can be successfully argued that it is scientifically justified. In general, researchers are required to consult with the institution's veterinarian and its Institutional Animal Care and Use Committee (IACUC), which every research facility is obliged to maintain. The IACUC must ensure that alternatives, including non-animal alternatives, have been considered, that the experiments are not unnecessarily duplicative, and that pain relief is given unless it would interfere with the study. Larry Carbone, a laboratory animal veterinarian, writes that, in his experience, IACUCs take their work very seriously regardless of the species involved, though the use of non-human primates always raises what he calls a "red flag of special concern."

Mice, rats, and birds are not included in the provisions of the Animal Welfare Act (though they are included in the Guide) and over the years, the definition of "animal" used by Congress and the United States Department of Agriculture (USDA) has changed several times to ensure that certain animals are included in protective legislation and that others, particularly farm animals, are excluded.

Numbers

Types of vertebrates used in animal testing in Europe in 2005: a total of 12.1 million animals were used.

Accurate global figures for animal testing are difficult to obtain. The British Union for the Abolition of Vivisection (BUAV) estimates that 100 million vertebrates are experimented on around the world every year, 10–11 million of them in the European Union. The Nuffield Council on Bioethics reports that global annual estimates range from 50 to 100 million animals.

None of the figures, including those given in this article, include invertebrates, such as shrimp and fruit flies. Animals bred for research then killed as surplus, animals used for breeding purposes, and animals not yet weaned (which most laboratories do not count) are also not included in the figures.

According to the U.S. Department of Agriculture (USDA), the total number of animals used in that country in 2005 was almost 1.2 million, but this does not include rats and mice, which make up about 90% of research animals. In 1995, researchers at Tufts University Center for Animals and Public Policy estimated that 14-21 million animals were used in American laboratories in 1992, a reduction from a high of 50 million used in 1970. In 1986, the U.S. Congress Office of Technology Assessment reported that estimates of the animals used in the U.S. range from 10 million to upwards of 100 million each year, and that their own best estimate was at least 17 million to 22 million.

In the UK, Home Office figures show that nearly three million procedures were carried out in 2004 on just under the same number of animals. It is the third consecutive annual rise and the highest figure since 1992. Most animals are used in only one procedure: animals either die because of the experiment or are euthanized afterwards. A "procedure" refers to an experiment that might last minutes, several months, or years.

Fruit flies are commonly used.

A white Wistar lab rat.

File:Beagle-inside-HLS.jpg A beagle inside Huntingdon Life Sciences.

Around 65,000 primates are used each year in the U.S. and Europe.

Species

• Invertebrates

Main article: Animal testing on invertebrates

Although much larger numbers of invertebrates than vertebrates are used, these experiments are largely unregulated by law. The most used invertebrate species are Drosophila melanogaster, a fruit fly, and Caenorhabditis elegans, a nematode worm. In the case of C. elegans, the worm's body is completely transparent and the precise lineage of all the organism's cells is known, while studies in the fly D. melanogaster can use an amazing array of genetic tools. These animals offer great advantages over vertebrates, including their short life cycle and the ease with which large numbers may be studied, with thousands of flies or nematodes fitting into a single room. However, the lack of an adaptive immune system and their simple organs prevent worms from being used in medical research such as vaccine development. Similarly, flies are not widely used in applied medical research, as their immune system differs greatly from that of humans, and diseases in insects can be very different from diseases in more complex animals.

• Rodents, fish, and rabbits

Main articles: Animal testing on rodents and Draize test

In the U.S., the numbers of rats and mice used is estimated at 20 million a year. Other rodents commonly used are guinea pigs, hamsters, and gerbils. Mice are the most commonly used vertebrate species because of their size, low cost, ease of handling, and fast reproduction rate. Mice are widely considered to be the best model of inherited human disease and share 99% of their genes with humans. With the advent of genetic engineering technology, genetically modified mice can be generated to order and can provide models for a range of human diseases.

Nearly 200,000 fish and 20,000 amphibians were used in the UK in 2004. The main species used is the zebrafish, Danio rerio, which are translucent during their embryonic stage, and the African clawed frog, Xenopus laevis. Over 20,000 rabbits were used for animal testing in the UK in 2004. Albino rabbits are used in eye irritancy tests because rabbits have less tear flow than other animals, and the lack of eye pigment make the effects easier to visualize.

• Cats and dogs

See also: Laika and Russian space dogs

Cats are most commonly used in neurological research. Over 25,500 cats were used in the U.S. in 2000, around half of whom were used in experiments that caused "pain and/or distress".

Dogs are widely used in biomedical research, testing, and education — particularly beagles, because they are gentle and easy to handle. They are commonly used as models for human diseases in cardiology, endocrinology, and bone and joint studies, research that tends to be highly invasive, according to the Humane Society of the United States. The U.S. Department of Agriculture's Animal Welfare Report for 2005 shows that 66,000 dogs were used in USDA-registered facilities in that year. In the U.S., some of the dogs are purpose-bred, while most are supplied by so-called Class B dealers licensed by the USDA to buy animals from auctions, shelters, newspaper ads, and who are sometimes accused of stealing pets.

• Non-human primates

Main article: Animal testing on non-human primates

Non-human primates (NHPs) are used in toxicology tests, studies of AIDS and hepatitis, studies of neurology, behavior and cognition, reproduction, genetics, and xenotransplantation. They are caught in the wild, taken from zoos, circuses and animal trainers, or purpose-bred. The primates used in the USA, China, and Europe are mostly purpose-bred. In the U.S. and China, most primates are domestically purpose-bred, whereas in Europe the majority are imported purpose-bred. Rhesus monkeys, cynomolgus monkeys, squirrel monkeys, and owl monkeys are imported; around 12,000 to 15,000 monkeys are imported into the U.S. annually. In total, around 70,000 NHPs are used each year in the United States and European Union. Most of the NHPs used are macaques; but marmosets, spider monkeys, and squirrel monkeys are also used, and baboons and chimpanzees are used in the U.S; in 2001 there were about 1,600 chimpanzees in U.S. research laboratories. Notable studies on non-human primates have been part of the polio vaccine development, and development of Deep Brain Stimulation, and their current heaviest non-toxicological use occurs in the monkey AIDS model, SIV.

Sources

Main articles: Laboratory animal sources and International trade in primates

Animals used by laboratories are largely supplied by specialist dealers. Sources differ for vertebrate and invertebrate animals. Most laboratories breed and raise flies and worms themselves, using strains and mutants supplied from a few main stock centers. For vertebrates, sources include breeders who supply purpose-bred animals; businesses that trade in wild animals; and dealers who supply animals sourced from pounds, auctions, and newspaper ads. Animal shelters also supply the laboratories directly. Large centers also exist to distribute strains of genetically-modified animals; the National Institutes of Health Knockout Mouse Project, for example, aims to provide knockout mice for every gene in the mouse genome.

In the U.S., Class A breeders are licensed by the U.S. Department of Agriculture (USDA) to sell animals for research purposes, while Class B dealers are licensed to buy animals from "random sources" such as auctions, pound seizure, and newspaper ads. Some Class B dealers have been accused of kidnapping pets and illegally trapping strays, a practice known as bunching. It was in part out of public concern over the sale of pets to research facilities that the 1966 Laboratory Animal Welfare Act was ushered in — the Senate Committee on Commerce reported in 1966 that stolen pets had been retrieved from Veterans Administration facilities, the Mayo Institute, the University of Pennsylvania, Stanford University, and Harvard and Yale Medical Schools. The USDA recovered at least a dozen stolen pets during a raid on a Class B dealer in Arkansas in 2003.

Four states in the U.S. — Minnesota, Utah, Oklahoma, and Iowa — require their shelters to provide animals to research facilities. Fourteen states explicitly prohibit the practice, while the remainder either allow it or have no relevant legislation.

In the European Union, animal sources are governed by Council Directive 86/609/EEC, which requires lab animals to be specially bred, unless the animal has been lawfully imported and is not a wild animal or a stray. The latter requirement may also be exempted by special arrangement. In the UK, most animals used in experiments are bred for the purpose under the 1988 Animal Protection Act, but wild-caught primates may be used if exceptional and specific justification can be established. The United States also allows the use of wild-caught primates; between 1995 and 1999, 1,580 wild baboons were imported into the U.S. Over half the primates imported between 1995 and 2000 were handled by Charles River Laboratories, Inc., or by Covance, which is the single largest importer of primates into the U.S.

Pain and suffering

Main article: Pain and suffering in laboratory animals

Further information: Animal cognition

The extent to which animal testing causes pain and suffering, and the capacity of animals to experience and comprehend them, is the subject of much debate.

According to the U.S. Department of Agriculture, in 2006 about 670,000 animals (not including rats, mice, birds, or invertebrates) were used in procedures that did not include more than momentary pain or distress. About 420,000 were used in procedures in which pain or distress was relieved by anesthesia, while 84,000 were used in studies that would cause pain or distress that would not be relieved.

In the UK, research projects are classified as mild, moderate, and substantial in terms of the suffering the researchers conducting the study say they may cause; a fourth category of "unclassified" means the animal was anesthetized and killed without recovering consciousness, according to the researchers. In December 2001, 39 percent (1,296) of project licences in force were classified as mild, 55 percent (1,811) as moderate, two percent (63) as substantial, and 4 percent (139) as unclassified. The Observer wrote in 2003 that the British Home Office worked with Imutran Ltd, a subsidiary of Novartis Pharma AG, to underestimate suffering in order to obtain licences to conduct kidney transplants on non-human primates. A report from the company said: "The Home Office will attempt to get the kidney transplants classified as 'moderate,' ensuring that it is easier for Imutran to receive a licence and ignoring the 'severe' nature of these programmes."

Larry Carbone, a laboratory animal veterinarian with the University of California, San Francisco, writes that the idea that animals might not feel pain as human beings feel it traces back to the 17th-century French philosopher, René Descartes, who argued that animals do not experience pain and suffering because they lack rationality. Bernard Rollin of Colorado State University, the principal author of two U.S. federal laws regulating pain relief for animals, writes that researchers continued to equivocate into the 1980s as to whether animals experience pain, and that veterinarians trained in the U.S. before 1989 were simply taught to ignore animal pain. In his interactions with scientists and other veterinarians, he was regularly asked to "prove" that animals are conscious, and to provide "scientifically acceptable" grounds for claiming that they feel pain.

Carbone writes that the view that animals feel pain differently is now a minority view, and that radical theories that fly in the face of common sense find little acceptance. Academic reviews of the topic are more equivocal, noting that although the argument that animals have at least simple conscious thoughts and feelings has strong support, some critics continue to question the validity of such theories. The ability of invertebrate species of animals, such as insects, to feel pain and suffering is also unclear. The majority of researchers do accept that animals feel pain, although at an individual level, Carbone has often experienced researchers denying that particular animals are in pain, even when they are standing together watching the animal's response to a scalpel or needle.

Researchers may remain reluctant to dispense pain medication for a number of reasons. Carbone writes that anesthetics and analgesics are expensive, and that many are controlled narcoleptics that require extensive record keeping, licencing, and — in the U.S. — Drug Enforcement Administration inspections. Correctly used, they would require round-the-clock attendance on the animals, and redosing every few hours, and they have side effects, such as respiratory depression, intestinal problems, and decreased blood clotting, that could impact on the research variables. There are also studies, such as the testing of painkillers, where the aim of the research is to assess pain. Carbone writes that he suspects that even researchers raised in the era of increased awareness of animal welfare may be inclined to under-diagnose and under-treat pain because they do not want to see themselves as people who inflict it.

Euthanasia

Further information: Euthanasia and Animal euthanasia

There is general agreement that animal life should not be taken wantonly, and regulations require that scientists use as few animals as possible. However, policy makers consider suffering to be the central issue, and see animal euthanasia as a way to reduce suffering, while others, such as the RSPCA, argue that the lives of laboratory animals have intrinsic value. Regulations focus on whether particular methods cause pain and suffering, not whether their death is undesirable in itself. Researchers call the killing of laboratory animals after an experiment "euthanasia" — literally "good death" — a term applied to all animals, including the young and healthy, although the same term is used of human beings only when the death will end severe suffering that cannot otherwise be relieved. The animals are euthanized at the end of studies for sample collection or post-mortem examination; during studies if their pain or suffering falls into certain categories regarded as unacceptable, such as depression, infection that is unresponsive to treatment, or the failure of large animals to eat for five days; or when they are unsuitable for breeding or unwanted for some other reason.

Methods of euthanizing laboratory animals are chosen to induce rapid unconsciousness and death without pain or distress. The methods that are preferred are those published by councils of veterinarians. The animal can be made to inhale a gas, such as carbon monoxide and carbon dioxide, by being placed in a chamber, or by use of a face mask, with or without prior sedation or anesthesia. Sedatives or anesthetics such as barbiturates can be given intraveneously, or inhalant anesthetics may be used. Amphibians and fish may be immersed in water containing an anesthetic such as tricaine. Physical methods are also used, with or without sedation or anesthesia depending on the method, particularly for small animals such as poultry, mice, small rats and rabbits, frogs, newborn kittens, and newborn puppies, though larger animals may also be killed by these methods. Recommended methods include decapitation (beheading) for small rodents or rabbits. Cervical dislocation (breaking the neck or spine) may be used for birds, mice, and immature rats and rabbits. Electrocution may be used for cattle, sheep, swine, foxes, and mink. However, it is only acceptable if the animals is unconscious before being electrocuted, which may be accomplished via a prior electrical stun. Maceration (grinding into small pieces) is used on 1 day old chicks. The physical method of pithing (inserting a tool into the base of the brain) is not acceptable as euthanasia. However, it may be used on an animal that is already unconscious. High-intensity microwave irradiation of the brain can preserve brain tissue and induce death in less than 1 second, but this is currently only used on rodents. Slow or rapid freezing, or inducing air embolism are not considered acceptable without prior anesthesia to induce unconsciousness. Captive bolts may be used, typically on dogs, ruminants, horses, pigs and rabbits. It causes death by a concussion to the brain. Gunshot may be used, but only in cases where a penetrating captive bolt may not be used.

Research classification

Pure research

Basic or pure research investigates how organisms behave, develop, and function. Those opposed to animal testing object that pure research may have little or no practical purpose, but researchers argue that it may produce unforeseen benefits, rendering the distinction between pure and applied research — research that has a specific practical aim — unclear.

Pure research uses larger numbers and a greater variety of animals than applied research. Fruit flies, nematode worms, mice and rats together account for the vast majority, though small numbers of other species are used, ranging from sea slugs through to armadillos.

Examples of the types of animals and experiments used in basic research include:

• Studies on embryogenesis and developmental biology. Mutants are created by adding transposons into their genomes, or specific genes are deleted by gene targeting. By studying the changes in development these changes produce, scientists aim to understand both how organisms normally develop, and what can go wrong in this process. These studies are particularly powerful since the basic controls of development, such as the homeobox genes, have similar functions in organisms as diverse as fruit flies and man.

• Experiments into behavior, to understand how organisms detect and interact with each other and their environment, in which fruit flies, worms, mice, and rats are all widely used. Studies of brain function, such as memory and social behavior, often use rats and birds. For some species, behavioral research is combined with enrichment strategies for animals in captivity because it allows them to engage in a wider range of activities.

• Breeding experiments to study evolution and genetics. Laboratory mice, flies, fish, and worms are inbred through many generations to create strains with defined characteristics. These provide animals of a known genetic background, an important tool for genetic analyses. Larger mammals are rarely bred specifically for such studies due to their slow rate of reproduction, though some scientists take advantage of inbred domesticated animals, such as dog or cattle breeds, for comparative purposes. Scientists studying how animals evolve use many animal species, including mosquitos, sticklebacks, and lampreys, to see how variations in where and how an organism lives (their niche) produce adaptations in their physiology and morphology.

Applied research

Applied research aims to solve specific and practical problems. Compared to pure research, which is largely academic in origin, applied research is usually carried out in the pharmaceutical industry, or by universities in commercial partnerships. These may involve the use of animal models of diseases or conditions, which are often discovered or generated by pure research programmes. In turn, such applied studies may be an early stage in the drug discovery process. Examples include:

• Genetic modification of animals to study disease. Transgenic animals have specific genes inserted, modified or removed, to mimic specific conditions such as single gene disorders, such as Huntington's disease. Other models mimic complex, multifactorial diseases with genetic components, such as diabetes, or even transgenic mice that carry the same mutations that occur during the development of cancer. These models allow investigations on how and why the disease develops, as well as providing ways to develop and test new treatments. The vast majority of these transgenic models of human disease are lines of mice, the mammalian species in which genetic modification is most efficient. Smaller numbers of other animals are also used, including rats, pigs, sheep, fish, birds, and amphibians.

• Studies on models of naturally occurring disease and condition. Certain domestic and wild animals have a natural propensity or predisposition for certain conditions that are also found in humans. Cats are used as a model to develop immunodeficiency virus vaccines and to study leukemia because their natural predisposition to FIV and Feline leukemia virus. Certain breeds of dog suffer from narcolepsy making them the major model used to study the human condition. Armadillos and humans are among only a few animal species that naturally suffer from leprosy; as the bacteria responsible for this disease cannot yet be grown in culture, armadillos are the primary source of bacilli used in leprosy vaccines.

Xenotransplantation

Main article: Xenotransplantation

Xenotransplantation involves transplanting living cells, tissues, or organs from one species to another. Current research involves using primates as the recipients of pig's organs. The British Home Office released figures in 1999 showing that 270 monkeys had been used in xeno research there during the previous four years. Documents leaked from Huntingdon Life Sciences to The Observer in 2003 showed, between 1994 and 2000, wild baboons were imported to the UK from Africa to be used in experiments that involved grafting pigs' hearts and kidneys onto the primates' necks, abdomens, and chests. The Observer reports that some baboons died after suffering strokes, vomiting, diarrhea, and paralysis, while others died en route to the UK. The experiments were conducted by Imutran Ltd, a subsidiary of Novartis Pharma AG in conjunction with Cambridge University and Huntingdon Life Sciences. Novartis told the newspaper that developing new cures for humans invariably means experimenting on live animals.

The newspaper also wrote that researchers were deliberately underestimating the suffering in order to obtain licences. A report from Imutran said: "The Home Office will attempt to get the kidney transplants classified as 'moderate,' ensuring that it is easier for Imutran to receive a licence and ignoring the 'severe' nature of these programmes."

Toxicology testing

Main article: Toxicology testing

Further information: Draize test, LD50, Acute toxicity, and Chronic toxicity

File:DraizeTest-PETA.jpg A rabbit during a Draize test. Source: PETA

File:LD50mouse.jpg A rat undergoing an LD50 test. Source: Animal Alliance

Toxicology testing, also known as safety testing, is conducted by pharmaceutical companies testing drugs, or by contract animal testing facilities, such as Huntingdon Life Sciences, on behalf of a wide variety of customers. According to 2005 EU figures, around one million animals are used every year in Europe in toxicology tests; which are about 10% of all procedures. According to Nature, 5,000 animals are used for each chemical being tested, with 12,000 needed to test pesticides. The tests are conducted without anesthesia, because interactions between drugs can affect how animals detoxify chemicals, and may interfere with the results.

Toxicology tests are used to examine finished products such as pesticides, medications, food additives, packing materials, and air freshener, or their chemical ingredients. Most tests involve testing ingredients rather than finished products, but according to BUAV, manufacturers believe these tests overestimate the toxic effects of substances; they therefore repeat the tests using their finished products to obtain a less toxic label.

The substances are applied to the skin or dripped into the eyes; injected intravenously, intramuscularly, or subcutaneously; inhaled either by placing a mask over the animals and restraining them, or by placing them in an inhalation chamber; or administered orally, through a tube into the stomach, or simply in the animal's food. Doses may be given once, repeated regularly for many months, or for the lifespan of the animal.

There are several different types of acute toxicity tests. The LD50 ("Lethal Dose 50%") test is used to evaluate the toxicity of a substance by determining the dose required to kill 50% of the test animal population. This test was removed from OECD international guidelines in 2002, replaced by methods such as the fixed dose procedure, which use fewer animals and cause less suffering. Nature writes that, as of 2005, "the LD50 acute toxicity test ... still accounts for one-third of all animal [toxicity] tests worldwide."

Irritancy is usually measured using the Draize test, where a test substance is applied to an animal's eyes or skin, usually an albino rabbit. For Draize eye testing, the recommended protocol involves observing the effects of the substance at intervals and grading any damage or irritation, but that the test should be halted and the animal killed if it shows "continuing signs of severe pain or distress". The Humane Society of the United States writes that the procedure can cause redness, ulceration, hemorrhaging, cloudiness, or even blindness. This test has also been criticized by scientists for being cruel and inaccurate, subjective, over-sensitive, and failing to reflect human exposures in the real world. Although no accepted in vitro alternatives exist, a modified form of the Draize test called the low volume eye test may reduce suffering and provide more realistic results, but it has not yet replaced the original test.

The most stringent tests are reserved for drugs and foodstuffs. For these, a number of tests are performed, lasting less than a month (acute), one to three months (subchronic), and more than three months (chronic) to test general toxicity (damage to organs), eye and skin irritancy, mutagenicity, carcinogenicity, teratogenicity, and reproductive problems. The cost of the full complement of tests is several million dollars per substance and it may take three or four years to complete.

These toxicity tests provide, in the words of a 2006 United States National Academy of Sciences report, "critical information for assessing hazard and risk potential". However, as Nature reported, most animal tests either over- or underestimate risk, or or do not reflect toxicity in humans particularly well. This variability stems from using the effects of high doses of chemicals in small numbers of laboratory animals to try to predict the effects of low doses in large numbers of humans. Although relationships do exist, opinion is divided on how to use data on one species to predict the exact level of risk in another.

Cosmetics testing

File:NoAnimalTesting.gif

Products in Europe not tested on animals carry this symbol.

Main article: Testing cosmetics on animals

Cosmetics testing on animals is particularly controversial. Such tests, which are still conducted in the U.S., involve general toxicity, eye and skin irritancy, phototoxicity (toxicity triggered by ultraviolet light) and mutagenicity.

Cosmetics testing is banned in the Netherlands, Belgium, and the UK, and in 2002, after 13 years of discussion, the European Union (EU) agreed to phase in a near-total ban on the sale of animal-tested cosmetics throughout the EU from 2009, and to ban all cosmetics-related animal testing. France, which is home to the world's largest cosmetics company, L'Oreal, has protested the proposed ban by lodging a case at the European Court of Justice in Luxembourg, asking that the ban be quashed. The ban is also opposed by the European Federation for Cosmetics Ingredients, which represents 70 companies in Switzerland, Belgium, France, Germany and Italy.

Drug testing

File:Dogs6CCcopy.jpg

Beagles used for safety testing of pharmaceuticals in a British facility, 2000. Provided by Research Defence Society/Wellcome Trust Photographic Library [2]

Before the early 20th century, laws regulating drugs were lax. For example, in the U.S., the government could only ban a drug after a company had been prosecuted for selling products that harmed customers. However, in response to a tragedy where a drug labeled “Elixir of Sulfanilamide” killed 73 people, the U.S. congress passed laws that required safety testing of drugs, before they could be marketed. Nowadays all new pharmaceuticals undergo rigorous animal testing before being licensed for human use. Tests on pharmaceutical products involve:

• metabolic tests, investigating pharmacokinetics - how drugs are absorbed, metabolized and excreted by the body when introduced orally, intravenously, intraperitoneally, intramuscularly, or transdermally.

File:Rodent52copy.jpg

A technician assessing mice in a typical research vivarium. Photo from the Research Defence Society/Wellcome Trust Photographic Library.

• toxicology tests, which gauge acute, sub-acute, and chronic toxicity. Acute toxicity is studied by using a rising dose until signs of toxicity become apparent. Current European legislation demands that "acute toxicity tests must be carried out in two or more mammalian species" covering "at least two different routes of administration". Sub-acute toxicity is where the drug is given to the animals for four to six weeks in doses below the level at which it causes rapid poisoning, in order to discover if any toxic drug metabolites build up over time. Testing for chronic toxicity can last up to two years and, in the European Union, is required to involve two species of mammals, one of which must be non-rodent.
• efficacy studies, which test whether experimental drugs work by inducing the appropriate illness in animals. The drug is then administered in a double-blind controlled trial, which allows researchers to determine the effect of the drug and the dose-response curve.
• Specific tests on reproductive function, embryonic toxicity, or carcinogenic potential can all be required by law, depending on the result of other studies and the type of drug being tested.

Education, breeding, and defense

Animals are also used for education and training; are bred for use in laboratories; and are used by the military to develop weapons, vaccines, battlefield surgical techniques, and defensive clothing.

There are efforts in many countries to find alternatives to using animals in education. Horst Spielmann, German director of the Central Office for Collecting and Assessing Alternatives to Animal Experimentation, while describing Germany's progress in this area, told German broadcaster ARD in 2005: "Using animals in teaching curricula is already superfluous. In many countries, one can become a doctor, vet or biologist without ever having performed an experiment on an animal."

Ethics

Further information: Animal rights

The ethics and point of performing experiments on animals are subject to much debate. There are disagreements about which animal testing procedures are useful for which purposes, as well as disagreements over which ethical principles apply, and to which species of animals. Some ethical positions consider that animals have an intrinsic right not to be experimented on, and that experiments should be conducted on humans who have given informed consent instead. Some opponents, particularly supporters of animal rights, argue further that any benefits to human beings cannot outweigh the suffering of the animals, and that human beings have no moral right to use an individual animal in ways that do not benefit that individual. The benefits of animal testing are also questioned, with organizations such as People for the Ethical Treatment of Animals stating that the suffering of the animals used in research is excessive in relation to whatever benefits may be reaped, and that in practice there is widespread abuse of animals.

Others take a utilitarian approach and try to weigh the positive and negative aspects of animal experiments; designing protocols and laws that attempt to maximize desirable results and minimize pain and suffering. In particular, proponents argue that it would be unethical to test substances or drugs with potentially adverse side-effects on human beings,[3] and that animals receive more sophisticated medical care because of animal tests that have led to advances in veterinary medicine.[4] The focus of public debate on this issue is also questioned, with over 10 times more animals are used by humans for other purposes (agriculture, hunting, pest control) than are used in animal testing. 100 million animals are killed by hunting each year. 150 million large mammals are used in agriculture each year. [5] Hundreds of millions of rats are involved in pest control. Over seven million dogs and cats are euthanized by animal shelters each year, and a million animals are killed each day by automobiles.

Validity of results

Many opponents of animal testing contend that it is not scientifically useful and persists because scientists have vested interests in maintaining the practice. [6] Many animal models of disease are induced, rather than naturally occurring, and it is argued that these are not comparable to human disease. For example, although genetic [7] and toxin-mediated animal models are now widely used to model Parkinson's disease, the British anti-vivisection interest group BUAV argues that these models only superficially resemble the disease symptoms, without the same time course or cellular pathology. In contrast, scientists assessing the usefulness of animal models of Parkinson's disease, as well as the medical research charity The Parkinson's Appeal, state that these models were invaluable and that they led to improved surgical treatments such as pallidotomy, new drug treatments such as levodopa, and later deep brain stimulation.

The conditions and experimental design of experiments determine the validity of results, or how generally the results can be applied. The BUAV argue that the laboratory environment and the experiments themselves are capable of affecting every organ and biochemical function in the body. "Noise, restraint, isolation, pain, psychological distress, overcrowding, regrouping, separation from mothers, sleeplessness, hypersexuality, surgery and anaesthesia can all increase mortality, contact sensitivity, tumour susceptibility and metastatic spread, as well as decrease viral resistance and immune response." [8]

Proponents of animal research argue that drugs and vaccines produced through animal testing are vital to modern medicine [9], that there have been several examples of substances causing death or injury to human beings because of inadequate animal testing [10], and that there are no known alternatives to many kinds of animal testing. They claim that anti-vivisection activists manipulate and fabricate facts so that their claims are not reliable.

Controlled experiments involve manipulating a single variable at a time, which is why animals used for experiments are housed in laboratory settings. In contrast, human environments and genetic backgrounds vary widely, which makes it difficult to control important variables for human subjects. [11] Animals can be bred especially for animal-testing purposes, meaning they arrive at the laboratory free from disease. Some animals (e.g. Drosophila) have shorter life and reproductive spans than humans, meaning that several generations can be studied in a relatively shorter time.

Advocates of animal research argue that there is no substitute for the living systems necessary to study interaction among cells, tissue, and organs. Animals are good surrogates because of their similarities to humans. [12] There is no substitute for studies of the infection of a host. For example, infection with hepatitis, malaria or treatment with monoclonal antibodies all have unique advantages in chimpanzees.

Controversy

File:It'sADog'sLife.gif Footage filmed by PETA inside Huntingdon Life Sciences in 1997 showed staff punching and screaming at beagles.

File:Covance Undercover 1.jpeg Filmed inside Covance for the BUAV.

File:Marmoset2.jpg A marmoset after being brain damaged, filmed inside Cambridge University by the BUAV.

File:Britchesbaby.jpg Filmed inside the University of California, Riverside by the Animal Liberation Front; the device on the monkey's head emitted a high-pitched noise every few minutes.

Highlighted cases

Huntingdon Life Sciences

Main article: Stop Huntingdon Animal Cruelty

In 1997, People for the Ethical Treatment of Animals (PETA) filmed staff inside Huntingdon Life Sciences (HLS) in the UK, Europe's largest animal-testing facility, hitting puppies, shouting at them, and simulating sex acts while taking blood samples. The employees were dismissed and prosecuted, and HLS's licence to perform animal experiments was revoked for six months. Footage shot inside HLS in the U.S. appeared to show technicians dissecting a live monkey. (video) The broadcast of the undercover footage on British television in 1997 triggered the formation of Stop Huntingdon Animal Cruelty, an international campaign to close HLS, which has been criticized for its sometimes violent tactics.

Covance

Main article: Covance

In 2004, German journalist Friedrich Mülln shot undercover footage of staff in Covance, Münster, Europe's largest primate-testing center, making monkeys dance in time to blaring pop music, handling them roughly, and screaming at them. The monkeys were kept isolated in small wire cages with little or no natural light, no environmental enrichment, and high noise levels from staff shouting and playing the radio (video). Primatologist Dr. Jane Goodall described the living conditions of the monkeys as "horrendous." Primatologist Stephen Brend told BUAV that using monkeys in such a stressed state is "bad science," and trying to extrapolate useful data in such circumstances an "untenable proposition." Covance obtained a restraining order preventing Mülln from performing any further undercover research against the company for three years, and required him and PETA to turn over the material they obtained from Covance. PETA is further prevented from attempting to infiltrate Covance for five years.

University of Cambridge

Main article: Primate experiments at Cambridge University

In February 2005, the British Union for the Abolition of Vivisection (BUAV) told the High Court in London that internal documents from the University of Cambridge's primate-testing labs showed that monkeys had undergone surgery to induce a stroke, and were left alone after the procedure for 15 hours overnight. Researchers had trained the monkeys to perform certain tasks before inflicting brain damage and re-testing them. The monkeys were deprived of food and water to encourage them to perform the tasks. The judge hearing BUAV's application for a judicial review rejected the allegation that the Home Secretary had been negligent in granting the university a license.

University of California, Riverside

Main article: Britches (monkey)

One of the cases of alleged abuse involved Britches, a macaque monkey born in 1985 at the University of California, Riverside, removed from his mother at birth, and left alone with his eyelids sewn shut, and a sonar device on his head, as part of a sight-deprivation experiment. 260 animals, including Britches, were stolen from the laboratories at the University of California, Riverside in a raid by the Animal Liberation Front. (video). The university alleged that damage to the monkey's eyelids, (see image), caused by the sutures according to the ALF, had in fact been caused by an ALF veterinarian, and that the sonar device had been removed and re-attached by the activists. The ALF reported that Britches was later transferred to a sanctuary in Mexico. University officials reported that hundreds of thousands of dollars of damage was done by the theft, and by smashing laboratory equipment, and years of medical research were lost.

Columbia University

Main article: Primate experiments at Columbia University

CNN reported in October 2003 that a post-doctoral "whistleblowing" veterinarian at Columbia University approached the university's Institutional Animal Care and Use Committee about experiments being carried out by an assistant professor of neurosurgery, E. Sander Connolly. [13] Connolly was allegedly causing strokes in baboons by removing their left eyeballs and using the eye sockets to reach a critical blood vessel to their brains. A clamp was placed on the blood vessel until the stroke was induced, after which Connolly would try to treat the condition with an experimental drug. In a letter to the National Institute of Health, PETA cited the case of one baboon left for two days unable to sit up or eat, who was slouched over in his cage and vomiting before dying. An investigation by the United States Department of Agriculture found the experiments did not violate federal guidelines. Connolly abandoned the research saying he felt under attack after receiving a threatening e-mail, but continued to believe his experiments were humane and potentially valuable.

Threats to researchers

University of California, Los Angeles

In 2006, a primate researcher at the University of California, Los Angeles (UCLA) shut down the experiments in his lab after threats from animal rights activists. The researcher had received a grant to use 30 macaque monkeys for vision experiments; each monkey was paralyzed, then used for a single session that lasted up to 120 hours, and finally killed. The researcher's name, phone number, and address were posted on the website of the Primate Freedom Project. Demonstrations were held in front of his home. A Molotov cocktail was placed on the porch of what was believed to be the home of another UCLA primate researcher; instead, it was accidentally left on the porch of an elderly woman unrelated to the university. The Animal Liberation Front claimed responsibility for the attack. [14] [15] As a result of the campaign, the researcher sent an email to the Primate Freedom Project stating "you win," and "please don’t bother my family anymore." [16] In another incident at UCLA in June 2007, the Animal Liberation Brigade placed a bomb under the car of a UCLA children's ophthalmologist who experiments on cats and rhesus monkeys; the bomb had a faulty fuse and did not detonate. UCLA is now refusing Freedom of Information Act requests for animal medical records.

Alternatives to animal testing

Main article: Alternatives to animal testing

Scientists and governments state that animal testing should cause as little suffering to animals as possible, and that animal tests should only be performed where necessary. The "three Rs" are guiding principles for the use of animals in research in most countries:

• Reduction refers to methods that enable researchers to obtain comparable levels of information from fewer animals, or to obtain more information from the same number of animals.
• Replacement refers to the preferred use of non-animal methods over animal methods whenever it is possible to achieve the same scientific aim.
• Refinement refers to methods that alleviate or minimize potential pain, suffering or distress, and enhance animal welfare for the animals still used.

Although such principles have been welcomed as a step forwards by some animal welfare groups, they have also been criticized as both outdated by current research, and of little practical effect in improving animal welfare.

See also

• Human experimentation
• Rat Park
• The People's Petition

Further reading and external links

• Stephens, Martin & Rowan, Andrew. Template:PDFlink, Humane Society of the United States, retrieved October 29, 2005
• 1940 American/Soviet film of dog resurrection experiments
• "Select Committee on Animals In Scientific Procedures Report", Select Committee on Animals in Scientific Procedures, British House of Lords, July 16, 2002, retrieved October 27, 2005.
• "Statistics of Scientific Procedures on Living Animals", Great Britain, 2004.
• "Why use animals?" and other FAQ, North Carolina Association for Biomedical Research, retrieved October 23, 2005
• "Basic statement", Aërzte gegen Tierversuche (Doctors against Animal Experiments], retrieved October 23, 2005.
• "Biomed for the layperson", Laboratory Primate Advocacy Group, retrieved February 24, 2006.
• In Focus "Animal Experiments in Research" (German Reference Centre for Ethics in the Life Sciences)
• Encyclopedia of Earth: Animal testing alternatives